The average age of the U.S. population continues to increase, causing a surge in the size of the geriatric population. While only 13% of US population is 65 and older, they consume over 36% of personal health expenditures. Cardiovascular disease (CVD) is a major contributor to both mortality and health care costs among elderly population. It is becoming evident that aging results in well-defined structural and functional changes in the blood vessel wall that render the cardiovascular system prone to disease even in the absence of traditional risk factors. Moreover, age-related alterations render the aged vasculature more susceptible to the damaging effects of the common CV risk factors. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging includes endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Recent findings suggest that age-related diseases could be delayed by modulating senescence. The Specific Aims of this proposal are designed to test the hypothesis that PAI-1 plays a critical role in the development of vascular senescence and physiological aging. Preliminary data presented here indicate that PAI-1 is not merely a marker of senescence but directly contributes to the molecular pathogenesis of senescence and aging in the cardiovascular system. We propose to use aging animals with global, as well as tissue- and function-specific PAI-1 deficiency, to delineate the involvement of PAI-1 in the age-related vascular remodeling. We will also address the effect of PAI-1 deficiency over the lifespan on the aging and senescence in a human population. We propose to study the Berne Amish community in Indiana, in which one of only 3 confirmed genetic defects associated with complete PAI-1 deficiency has been described. We anticipate that these studies will not only establish the role of PAI-1 in senescence, but will also advance our knowledge of the mechanisms that drive physiological aging. Furthermore, understanding the molecular mechanism of PAI-1's role in senescence and aging may provide new insights into the prevention and treatment of aging-related dysfunction and frailty.